Process for the synthesis of 3-hydroxyglutaronitrile

ABSTRACT

A high yield and high productivity processes for preparing 3-hydroxyglutaronitrile by reacting an epihalohydrin or a 4-halo-3-hydroxy-butanenitrile, or analogous compound containing a different leaving group, with cyanide (CN—) in the presence of water and an ionic liquid. The use of an ionic liquid as a cosolvent with water results in increased productivity and selectivity.

This application is a Divisional of U.S. application Ser. No. 12/518,317now U.S. Pat. No. 8,268,960, and claims the benefit of U.S. ProvisionalApplication No. 60/874,401, filed 12 Dec. 2007, which is incorporated inits entirety as a part hereof for all purposes.

TECHNICAL FIELD

This invention relates to the manufacture of 3-hydroxyglutaronitrile,which is a useful intermediate in chemical synthesis.

BACKGROUND

The compound 3-hydroxyglutaronitrile (“3-HGN”) is a precursor for avariety of useful materials, such as pharmaceutically active compounds,diamines used in hair coloring, and monomers for high-strength fibers.It has conventionally been synthesized by treating epichlorohydrin(“ECH”) with an inorganic cyanide in water, producing4-chloro-3-hydroxy-butanenitrile (also known as “chlorohydrin”) as anintermediate, as shown for example by F. Johnson et al, J. Org. Chem.(1962), 27, 2241-2243):

This process suffers from low productivity and byproduct formation. Forexample, Johnson et al reported 60% yield after about 54 hours reactiontime at 10-11° C. and 48 hours of continual extraction with ethylacetate. Significant byproducts (18%) included the intermediate4-chloro-3-hydroxy-butanenitrile and 4-hydroxycrotononitrile.

A need thus remains for a process to synthesize 3-hydroxyglutaronitrilewith increased productivity and selectivity.

SUMMARY

The inventions disclosed herein include processes for the preparation of3-hydroxyglutaronitrile, processes for the preparation of products intowhich 3-hydroxyglutaronitrile can be converted, and the productsobtained and obtainable by such processes.

This invention thus provides high yield and high productivity processesfor preparing 3-hydroxyglutaronitrile by reacting an epihalohydrin or a4-halo-3-hydroxy-butanenitrile, or a compound that is analogous to thosestarting materials, respectively, in which the leaving group is otherthan a halogen, with cyanide (CN—) in the presence of water and an ionicliquid. The use of an ionic liquid as a cosolvent with water results inincreased productivity and selectivity.

One embodiment of the processes hereof provides a process for preparing3-hydroxyglutaronitrile by (a) providing an aqueous solution of a CN—source; (b) adjusting the pH of the solution to about 8-10; (c) addingto the solution a compound as described generally by Formula (I):

wherein X is a leaving group; (d) adding an ionic liquid and,optionally, a phase transfer catalyst to the solution; and (e) addingadditional CN— continuously at a rate at which the pH of the solution ismaintained at less than about 12, or discontinuously in more than onediscrete portion.

Another embodiment of the processes hereof provides a process forpreparing 3-hydroxyglutaronitrile by:

a. providing a biphasic mixture of water and an ionic liquid;

b. adding to the mixture a compound as described generally by Formula(II):

wherein X is a leaving group;

c. adding a CN— source and, optionally, a phase transfer catalyst to themixture; and

d. adding additional CN— continuously at a rate at which the pH of thesolution is maintained as less than about 12, or discontinuously in morethan one discrete portion.

DETAILED DESCRIPTION

One embodiment of this invention provides a process for preparing3-hydroxyglutaronitrile (“3-HGN”) comprising the sequential steps:

a. providing an aqueous solution of a CN— source;

b. adjusting the pH of the solution to about 8 to about 10;

c. adding to the solution (i) an epihalohydrin (I):

wherein X is a leaving group such as Cl, Br or I, or (ii) a compoundchat is analogous to she epihalohydrin in which X is a leaving groupother than a halogen;

d. adding an ionic liquid, and optionally a phase transfer catalyst, tothe solution;

e. adding additional CN— continuously at rate at which the pH of thereaction mixture is maintained at less than about 12, or discontinuouslyin more than one discrete portion.

The 3-HGN product may, as desired, be isolated and recovered, or may besubjected directly to further steps to convert it to another product,such as another compound or a monomer, or an oligomer or a polymerformed therefrom.

The process is represented schematically below:

The use of an ionic liquid cosolvent increases process productivity byshortening the reaction time without a detrimental effect in yield.Cyanide is introduced continuously at a rate at which the pH of thereaction mixture is maintained at pH of less than about 12, or less thanabout 11, or in the range of about 9.5 to about 10.5; or discontinuouslyin more than one discrete portion. High pH degrades, or reduces thecontent in the reaction mixture of, the 3-hydroxy-butanenitrileintermediate. A convenient way to avoid high pH is to add the cyanide inportions. Other than avoiding a high pH, rigorous pH control during thereaction is thus not necessary when the cyanide is added in portions.Portions such as tenths, eighths or sixths have been found suitable, butthe portions need not be equal in size. The intervals at which thevarious portions may be added may be an amount of time in the range ofabout 10 to about 80 minutes, or about 15 to about 60 minutes, or about15 to about 30 minutes; but the intervals need not be equal length oftime.

The aqueous solution provided in step (a) contains about 1 to about 1.5,preferably about 1.1 to about 1.3, moles of CN— for each mole ofepihalohydrin (or analogous compound) that is to be added in step (c).Suitable CN— sources include without limitation alkali cyanides such asKCN, NaCN and LiCN; and trimethylsilyl cyanide. Acetone cyanohydrin maybe used, in which case a base such as triethylamine is added with it inrelative amounts such that more than one mole of acetone cyanohydrin isadded per mole of base, or about 3 to about 4 moles of acetonecyanohydrin are added per mole of base.

The pH of the aqueous cyanide solution is then adjusted in step (b) byadding enough acid to lower the pH to the range of about 8 to about 10.A pH of about 8 is preferred. The specific acid used in step (b) is notcritical; examples include but are not limited, to H₂SO₄ and HCl.

In step (c), an epihalohydrin is added to the aqueous cyanide solutionand allowed to react with the CN— source for a time sufficient toproduce a 4-halo-3-hydroxy-butanenitrile [as described generally byFormula (II) when X is a halogen leaving group such as Cl, Br or I] asan intermediate, a sufficient time being, for example, about 10 to about12 hours:

Alternatively, in step (c) a compound could be added that is analogousto an epihalohydrin, an analogous compound being one that has the samestructure as an epihalohydrin, but has a leaving group that is not ahalogen and is instead a group such as acetate, tosylate or mesylate. Aleaving group in this context is a group that is readily displaced bythe CN— ion. In such case, X in Formula I and Formula II will representthe alternative leaving group instead of the halogen, and referencesherein to epihalohydrin and to 4-halo-3-hydroxy-butanenitrile should beunderstood to include references to the relevant compounds created whenX is a leaving group other than a halogen.

Epichlorohydrin is the preferred epihalohydrin and is readily availablecommercially. Epibromohydrin can be synthesized by epoxidation of pureor mixed dibromopropanol isomers [see, e.g., J. Manaf and R. Audinos,Bull. Soc. Chim. Er. (1997) 134, 93-100; and G. Braun, J. Amer. Chem.Soc. (1930), 52, 3167-76]. Epibromohydrin (98% purity) is alsocommercially available from the Aldrich Chemical Company (Milwaukee,Wis., USA). Epiiodohydrin can be synthesized, for example, by reactionof epichlorohydrin with aqueous potassium iodide [D. Liu et al, HarbinLigong Daxue Xuebao (1996), 1(3), 96-99]. Epiiodohydrin (X═I) andepibromohydrin (X═Br) can be synthesized by reaction of epichlorohydrinwith KX in the presence of catalytic amounts of the crown ether18-crown-6 [Y. Kawakami and Y. Yamashita, J. Org. Chem. (1980), 45(19),3930-2].

Exemplary compounds with alternative leaving groups are also availablein accordance with known processes. Suitable methods for preparing anacetoxy epoxide include those disclosed, for example, in the followingsources:

Catalyst-free gas-phase epoxidation of alkenes; Berndt, Torsten andBoege, Olaf; Leibniz-Institut fuer Troposphaerenforschung e.V., Leipzig,Germany; Chemistry Letters (2005), 34(4), 584-585; Publisher: ChemicalSociety of Japan.

Regioselective opening of an oxirane system with trifluoroaceticanhydride, A general method for the synthesis of 2-monoacyl- and1,3-symmetrical triacylglycerols; Stamatov, Stephan D. and Stawinski,Jacek; Department of Chemical Technology, University of Plovdiv,Plovdiv, Bulgaria; Tetrahedron (2005), 61(15), 3659-3669; Publisher:Elsevier B. V.

Novel synthesis and enzymatic resolution of (±)-2,3-epoxy propyl esters;Nair, Ranjeet V., Patil, Prashant N., and Salunkhe, Manikrao M.;Department of Chemistry, The Institute of Science, Mumbai, India;Synthetic Communications (1999), 29(15), 2559-2566; Publisher: MarcelDekker, Inc.

Organotin templates in organic reactions; 7. A convenient synthesis ofglycidyl esters (2,3-epoxypropyl alkanoates); Otera, Junzo andMatsuzaki, Shinjiro; Okayama Univ. Sci., Okayama, Japan; Synthesis(1986), (12), 1019-20.

Suitable methods for preparing an tosyloxy epoxide include thosedisclosed, for example, in the following sources:

Palladium-catalyzed synthesis of tetrahydrofurans from g-hydroxyterminal alkenes: Scope, limitations, and stereoselectivity; Hay,Michael B., Hardin, Alison R., and Wolfe, John P., Department ofChemistry, University of Michigan, Ann Arbor, Mich., USA; Journal ofOrganic Chemistry (2005), 70(8), 3099-3107; Publisher: American ChemicalSociety.

Poly(per)fluoroalkanesulfonyl fluoride-promoted olefin epoxidation with30% aqueous hydrogen peroxide; Yan, Zhaohua and Tian, Weisheng; ShanghaiInstitute of Organic Chemistry, Laboratory of Organofluorine Chemistry,Chinese Academy of Sciences, Shanghai, Peop. Rep. China; TetrahedronLetters (2004), 45(10), 2211-2213; Publisher: Elsevier Science B.V.

Process for producing glycidyl sulfonate derivatives by cyclization andsulfonation; Sakata, Midori, Furukawa, Yoshiro, Takenaka, and Keishi;Daiso Co., Ltd., Japan; WO 97/26254 A1 19970724.

Suitable methods for preparing a mesyloxy epoxide include thosedisclosed, for example, in Process and catalysts for the manufacture ofepoxy sulfonates; Schroeder, Georg, Arlt, Dieter, and Jautelat, Manfred;Bayer A.-G., Germany; EP 412,359 A1 19910213.

A suitable temperature of the aqueous solution in steps (a), (b) and (c)may be, for example, in the range of about 0 to about 25° C. For step(d), if the solution is not already at ambient temperature prior to step(d), it is typically allowed to come to ambient temperature;alternatively, it may be brought to temperature by gentle heating.Temperatures higher than about 25° C. may result in faster reaction butlower yield of 3-HGN.

In step (d), an ionic liquid cosolvent or a mixture of ionic liquids,and optionally a phase transfer catalyst (“PTC”), are added at ambienttemperature, and the resulting mixture is heated for an additional timeperiod. Heating to about 40 to about 65° C. for a period of up to about1 hour has been found suitable.

An ionic liquid is a liquid composed entirely of ions that is fluid atabout or below 100° C., as more particularly described in Science (2003)302:792-793. Ionic liquids are typically organic salts. In the processof this invention, it is preferred but not required that the ionicliquid not be soluble in water. Examples of suitable ionic liquidsinclude without limitation 1-butyl-3-methylimidazoliumhexafluorophosphate (“[BMIM]PF₆”), 1-butyl-3-methylimidazolium2-H-perfluoropropane sulfonate, 1-butyl-3-methylimidazoliumtetrafluoroborate (“[BMIM]BF₄”), 1-ethyl-3-methylimidazolium1,1,2-trifluoro-2-(pentafluoroethoxy)-ethanesulfonate, and1-hexyl-3-methylimidazolium hexafluorophosphate. [BMIM]PF₆ is preferred.Other ionic liquids suitable for use herein are disclosed in U.S.2006/0197053, which is incorporated in its entirety as a part hereof forall purposes, and in the references cited therein. The volume of ionicliquid added is about the same as the volume of water in step (a).

A phase transfer catalyst suitable for use herein includes one or moremembers of a class of known substances that enhances the rate ofreaction between chemical species located in different phases (forexample, immiscible liquids) by extracting one of the reactants, mostcommonly an anion, across the interface into the other phase so thatreaction can proceed. Phase transfer catalysts are typically salts of“onium ions” (for example, tetraalkylammonium salts) or agents that cancomplex inorganic cations (for example, crown ethers). Examples ofsuitable phase transfer catalysts include without limitationtetraalkylammonium salts such as tetrabutylammonium iodide (“TBAI”) andspecific crown ethers as indicated by the size of the cation if the CN—source is an alkali cyanide (for example, 18-crown-6 for K+ when KCN isthe cyanide source). TBAI is preferred. In the absence of a phasetransfer catalyst, 3-HGN may be produced in lower yield; thus, use of aphase transfer catalyst is optional but preferred. When used, the amountof phase transfer catalyst is about 0.01 to about 0.10 mol, preferablyabout 0.05 to 0.1 mol, per mol of epihalohydrin.

In step (e), CN— is typically added such that the total amount of CN—added in steps (a) and (e) combined is at least about 2.05 moles of CN—per mole of epihalohydrin added in step (c). For example, if the aqueoussolution in step (a) is made with about 1.25 moles of CN— and in step(c) about 1 mole of epihalohydrin is added, then at least an additional0.80 moles of CN— will typically be added in step (e). Cyanide is alsointroduced continuously at a rate at which the pH of the reactionmixture is maintained at pH of less than about 12, or less than about11, or in the range of about 9.5 to about 10.5; or discontinuously inmore than one discrete potion. A convenient way to avoid high pH is toadd the cyanide in portions. Other than avoiding a high pH, rigorous pHcontrol during the reaction is thus not necessary when the cyanide isadded in portions. Portions such as tenths, eighths or sixths have beenfound suitable, but the portions need not be equal in size. Theintervals at which portions may be added may be an amount of time in therange of about 10 to about 80 minutes, or about 15 to about 60 minutes,or about 15 to about 30 minutes; but the intervals need not be equal inlength of time. In the case mentioned above, for example, the 0.80 molescould be divided into, e.g., 8 portions, each containing 0.10 mole CN—,and one portion could be added every 15 to 30 minutes until all 8portions had been added.

After the last addition of CN—, the mixture is stirred with heating foran additional time period. Temperatures in the range of about 45 toabout 65° C. for a period of about 45 min to about 2 h have been foundsuitable. The reaction mixture is then cooled to allow the organic andaqueous layers to separate. In general, the 3-HGN product resideslargely in the aqueous phase, and the water layer may thus be extractedwith, for example, ethyl acetate, tetrahydrofuran (“THF”),cyclopentanone, cyclohexanone, or methylethylketone (“MEK”). The organicextracts are concentrated, and the residue is purified by any suitablemeans known in the art (for example, column chromatography) to yield theproduct 3-HGN as a yellow oil.

The 3-HGN product may, as desired, be isolated and recovered, or may besubjected directly to further steps to convert it to another product,such as another compound or an oligomer or a polymer.

A second embodiment of this invention provides a process for preparing3-hydroxyglutaronitrile comprising the sequential steps:

a. providing a biphasic mixture of water and an ionic liquid;

b. adding to the mixture (i) a 4-halo-3-hydroxy-butanenitrile:

wherein X is a leaving group such as Cl, Br or I, or (ii) a compoundthat is analogous to the 4-halo-3-hydroxy-butanenitrile in which X is aleaving group other than a halogen;

c. adding a CN— source, and optionally a phase transfer catalyst, to themixture; and

d. adding additional CN— continuously at a rate at which the pH of thereaction mixture is maintained at less than about 12, or discontinuouslyin more than one discrete portion.

As discussed above, ionic liquids that are not soluble in water arepreferred, but not required, for use in step (a). [BMIM]PF₆ is asuitable choice as the ionic liquid. The volume of ionic liquid in thebiphasic mixture is about the same as the volume of water.

A 4-halo-3-hydroxy-butanenitrile (II) for addition in step (b) can beproduced by reacting the corresponding epoxide with LiX (X═Cl, Br or I)as described in Bajwa et al, Tetrahedron Letters (1991), 32(26), 3021-4;or with HCN in the presence of a sulfate, nitrate and/or phosphate of analkali metal or alkaline earth metal in water as described in JP2002/241,357. 4-chloro-3-hydroxybutanenitrile is preferred and iscommercially available.

Alternatively, in step (b) a compound could be added that is analogousto a 4-halo-3-hydroxy-butanenitrile, an analogous compound being onethat has the same structure as a 4-halo-3-hydroxy-butanenitrile, but hasa leaving group that is not a halogen and is instead a group such asacetate, tosylate or mesylate. A leaving group in this context is agroup that is readily displaced by the CN— ion. In such case, X inFormula II will represent the alternative leaving group instead of thehalogen, and references herein to 4-halo-3-hydroxy-butanenitrile shouldbe understood to include references to the relevant compounds createdwhen X is a leaving group other than a halogen.

A suitable CN— source, and the optional phase transfer catalyst, foraddition in step (c) are as described above. KCN is preferred, and theuse of TBAI as a phase transfer catalyst is preferred. The mixtureproduced in step (c) is heated, and heating to a temperature in therange of about 40 to about 65° C. has been found suitable for thispurpose.

In step (d), CN— is added in an amount such that the total amount of CN—added in steps (c) and (d) combined is at least about 2.05 moles of CN—per mole of 4-halo-3-hydroxy-butanenitrile (or analogous compound with anon-halogen leaving group) added in step (b). Cyanide is introducedcontinuously at a rate at which the pH of the reaction mixture ismaintained at ph of less than about 12, or less than about 11, or in therange of about 9.5 to about 10.5; or discontinuously in more than onediscrete portion. Portions such as tenths, eighths or sixths have beenfound suitable, but the portions need not be equal in size. Theintervals at which portions may be added may be an amount of time in therange of about 10 to about 80 minutes, or about 15 to about 60 minutes,or about 15 to about 30 minutes; but the intervals need not be equal inlength of time.

After the last addition of CN—, the mixture is stirred with heating foran additional time period. Temperatures in the range of about 45 toabout 65° C. for a period of about 45 min to about 2 h have been foundsuitable. The reaction mixture is then cooled to allow the organic andaqueous layers to separate. In general, the 3-HGN product resideslargely in the aqueous phase, and the water layer may thus be extractedwith, for example, ethyl acetate, tetrahydrofuran (“THF”),cyclopentanone, cyclohexanone, or methylethylketone (“MEK”). The organicextracts are concentrated, and the residue is purified by any suitablemeans known in the art (for example, column chromatography) to yield theproduct 3-HGN as a yellow oil.

The 3-HGN product may, as desired, be isolated and recovered asdescribed above. It may also be subjected with or without recovery fromthe reaction mixture to further steps to convert it to another productsuch as another compound (e.g. a monomer), or an oligomer or a polymer.Another embodiment of a process hereof thus provides a process forconverting 3-HGN, through one or more reactions, into another compound,or into an oligomer or a polymer. 3-HGN may be made by a process such asdescribed above, and then converted, for example, into a compound suchas a diaminopyridine. In a multi-step process, a diaminopyridine may inturn be subjected to a polymerization reaction to prepare an oligomer orpolymer therefrom, such as those having amide functionality, imidefunctionality, or urea functionality, or apyridobisimidazole-2,6-diyl(2,5-dihydroxy-p-phenylene)polymer.

3-HGN may be converted into a diaminopyridine by a process in which3-HGN is reacted with ammonia or an ammonium donor such as an aliphatic,cyclic or aromatic amine, including amines such as n-butylamine,benzylamine, piperazine and aniline. The reaction is carried out in asolvent such as an alcohol at a temperature of 100-200° C., with thepreferable use of a transition metal catalyst such as copper, cobalt,manganese or zinc salt. A process similar to the foregoing is describedin U.S. Pat. No. 5,939,553.

A diaminopyridine (and thus ultimately 3-HGN as its precursor) may beconverted into a polyamide oligomer or polymer by reaction with a diacid(or diacid halide) in a process in which, for example, thepolymerization takes place in solution in an organic compound that isliquid under the conditions of the reaction, is a solvent for both thediacid (halide) and the diaminopyridine, and has a swelling or partialsalvation action on the polymeric product. The reaction may be effectedat moderate temperatures, e.g. under 100° C., and is preferably effectedin the presence of an acid acceptor that is also soluble in the chosensolvent. Suitable solvents include methyl ethyl ketone, acetonitrile,N,N-dimethylacetamide dimethyl formamide containing 5% lithium chloride,and N-methyl pyrrolidone containing a quaternary ammonium chloride suchas methyl tri-n-butyl ammonium chloride or methyl-tri-n-propyl ammoniumchloride. Combination of the reactant components causes generation ofconsiderable heat and the agitation, also, results in generation of heatenergy. For that reason, the solvent system and other materials arecooled at all times during the process when cooling is necessary tomaintain the desired temperature. Processes similar to the foregoing aredescribed in U.S. Pat. No. 3,554,966; U.S. Pat. No. 4,737,571; and CA2,355,316.

A diaminopyridine (and thus ultimately 3-HGN as its precursor) may alsobe converted into a polyamide oligomer or polymer by reaction with adiacid (or diacid halide) in a process in which, for example, a solutionof the diaminopyridine in a solvent may be contacted in the presence ofan acid acceptor with a solution of a diacid or diacid halide, such as adiacid chloride, in a second solvent that is immiscible with the firstto effect polymerization at the interface of the two phases. Thediaminopyridine may, for example, be dissolved or dispersed in a watercontaining base with the base being used in sufficient quantities toneutralize the acid generated during polymerization. Sodium hydroxidemay be used as the acid acceptor. Preferred solvents for thediacid(halide) are tetrachloroethylene, methylenechloride, naphtha andchloroform. The solvent for the diacid(halide) should be a relativenon-solvent for the amide reaction product, and be relatively immisciblein the amine solvent. A preferred threshold of immiscibility is asfollows: an organic solvent should be soluble in the amine solvent notmore than between 0.01 weight percent and 1.0 weight percent. Thediaminopyridine, base and water are added together and vigorouslystirred. High shearing action of the stirrer is important. The solutionof acid chloride is added to the aqueous slurry. Contacting is generallycarried out at from 0° C. to 60° C., for example, for from about 1second to 10 minutes, and preferably from 5 seconds to 5 minutes at roomtemperature. Polymerization occurs rapidly. Processes similar to theforegoing are described in U.S. Pat. No. 3,554,966 and U.S. Pat. No.5,693,227.

A diaminopyridine (and thus ultimately 3-HGN as its precursor) may alsobe converted into a polyimide oligomer or polymer by reaction with atetraacid (or halide derivative thereof) or a dianhydride in a processin which each reagent (typically in equimolar amounts) is dissolved in acommon solvent, and the mixture is heated to a temperature in the rangeof 100˜250° C. until the product has a viscosity in the range of 0.1˜2dL/g. Suitable acids or anhydrides include benzhydrol3,3′,4,4′-tetracarboxylic acid, 1,4-bis(2,3-dicarboxyphenoxy)benzenedianhydride, and 3,3′,4,4′-benzophenone tetracarboxylic aciddianhydride. Suitable solvents include cresol, xylenol, diethyleneglycoldiether, gamma-butyrolactone and tetramethylenesulfone. Alternatively, apolyamide-acid product may be recovered from the reaction mixture andadvanced to a polyimide by heating with a dehydrating agent such as amixture of acetic anhydride and beta picoline. Processes similar to theforegoing are described in U.S. Pat. No. 4,153,783; U.S. Pat. No.4,736,015; and U.S. Pat. No. 5,061,784.

A diaminopyridine (and thus ultimately 3-HGN as its precursor) may alsobe converted into a polyurea oligomer or polymer by reaction with apolyisocyanate, representative examples of which include toluenediisocyanate; methylene bis(phenyl isocyanates); hexamethylenediisocycanates; phenylene diisocyanates. The reaction may be run insolution, such as by dissolving both reagents in a mixture oftetramethylene sulfone and chloroform with vigorous stirring at ambienttemperature. The product can be worked up by separation with water, oracetone and water, and then dried in a vacuum oven. Processes similar tothe foregoing are described in U.S. Pat. No. 4,451,642 and Kumar,Macromolecules 17, 2463 (1984). The polyurea forming reaction may alsobe run under interfacial conditions, such as by dissolving thediaminopyridine in an aqueous liquid, usually with an acid acceptor or abuffer. The polyisocyanate is dissolved in an organic liquid such asbenzene, toluene or cyclohexane. The polymer product forms at theinterface of the two phases upon vigourous stirring. Processes similarto the foregoing are described in U.S. Pat. No. 4,110,412 and Millichand Carraher, Interfacial Syntheses, Vol. 2, Dekker, N.Y., 1977. Adiaminopyridine may also be converted into a polyurea by reaction withphosgene, such as in an interfacial process as described in U.S. Pat.No. 2,816,879.

A diaminopyridine (and thus ultimately 3-HGN as its precursor) may alsobe converted into apyridobisimidazole-2,6-diyl(2,5-dihydroxy-p-phenylene) polymer by (i)converting the diaminopyridine to a diamino dinitropyridine, (ii)converting the diamino dinitropyridine to a tetraamino pyridine, and(iii) converting the tetraamino pyridine to apyridobisimidazole-2,6-diyl(2,5-dihydroxy-p-phenylene)polymer.

A diaminopyridine (and thus ultimately 3-HGN as its precursor) may beconverted to a diamino dinitropyridine by contacting it with nitric acidand a solution of sulfur trioxide in oleum, as discussed in WO 97/11058.A diamino dinitropyridine may be converted to a tetraamino pyridine byhydrogenation using a hydrogenation catalyst in the presence of a strongacid, and using a cosolvent such as a lower alcohol, an alkoxyalcohol,acetic acid or propionic acid, as discussed in U.S. Pat. No. 3,943,125.

A tetraamino pyridine (and thus ultimately 3-HGN as its precursor) maybe converted to a pyridobisimidazole-2,6-diyl(2,5-dihydroxy-p-phenylene)polymer by polymerizing a 2,5-dihydroxyterephthalic acid with thetrihydrochloride-monohydrate of tetraaminopyridine in strongpolyphosphoric acid under slow heating above 100° C. up to about 180° C.under reduced presuure, followed by precipitation in water, as disclosedin U.S. Pat. No. 5,674,969 (which is incorporated in its entirety as apart hereof for all purposes); or by mixing the monomers at atemperature from about 50° C. to about 110° C., and then 115° C. to forman oligomer, and then reacting the oligomer at a temperature of about160° C. to about 250° C. as disclosed in U.S. Provisional ApplicationNo. 60/665,737, filed Mar. 28, 2005 (which is incorporated in itsentirety as a part hereof for all purposes), published as WO2006/104974. Thepyridobisimidazole-2,6-diyl(2,5-dihydroxy-p-phenylene)polymer soproduced may be, for example, apoly(1,4-(2,5-dihydroxy)phenylene-2,6-pyrido[2,3-d:5,6-d′]bisimidazole)polymer, or apoly[(1,4-dihydrodiimidazo[4,5-b:4′,5′-e]pyridine-2,6-diyl)(2,5-dihydroxy-1,4-phenylene)]polymer. The pyridobisimidazole portionthereof may, however, be replaced by any or more of a benzobisimidazole,benzobisthiazole, benzobisoxazole, pyridobisthiazole and apyridobisoxazole; and the 2,5-dihydroxy-p-phenylene portion thereof maybe replaced by the derivative of one or more of isophthalic acid,terephthalic acid, 2,5-pyridine dicarboxylic acid, 2,6-naphthalenedicarboxylic acid, 4,4′-diphenyl dicarboxylic acid, 2,6-quinolinedicarboxylic acid, and 2,6-bis(4-carboxyphenyl)pyridobisimidazole.

EXAMPLES

The advantageous attributes and effects of the processes hereof may beseen in a series of examples (Examples 1˜7), as described below. Theembodiments of these processes on which these examples are based areillustrative only, and the selection of these embodiments to illustratethe invention does not indicate that conditions, arrangements,approaches, regimes, techniques, protocols and reactants not describedin these examples are not suitable for practicing these processes, orthat subject matter not described in these examples is excluded from thescope of the appended claims and equivalents thereof. The significanceof the examples is better understood by comparing the results obtainedtherefrom with the results obtained from a reaction that was designed noserve as a controlled experiment (Control A) and provide a basis forsuch comparison since an ionic liquid was not used during the reaction.

The following materials were used in the examples. All commercialreagents were used as received.

Tetrabutylammonium iodide (98% purity), acetone cyanohydrin (99%purity), triethyl amine (99.5% purity) and epichlorohydrin (99% purity)were obtained from the Aldrich Chemical Company (Milwaukee, Wis., USA).

Potassium cyanide (97% purity) was obtained from Sigma-Aldrich (St.Louis, Mo., USA).

1-butyl-3-methylimidazolium hexafluorophosphate (purity not specified)and 1-hexyl-3-methylimidazolium hexafluorophosphate (purity notspecified) were obtained from Acros Organic (Geel, Belgium).

4-chloro-3-hydroxybutanenitrile was synthesized from epichlorohydrin andone equivalent of cyanide as follows: Sodium cyanide (9.93 g) wasdissolved in 60 mL of water, and the solution was cooled to 0 C. To thissolution was added concentrated sulfuric acid, dropwise, until the pH ofthe solution was 8.5. Epichlorohydrin (15 g) was then added dropwise,and the mixture was allowed to reach room temperature overnight. Thereaction mixture was then extracted three times with ethyl acetate,dried over sodium sulfate, filtered and concentrated in vacuo. 18.5 g(96% isolated yield) of 4-chloro-3-hydroxybutanenitrile was obtained.The purity was at least 95%, the limit of the NMR measurement.

1-Butyl-3-methylimidazolium 2-H-perfluoropropane sulfonate wassynthesized by reacting 1-butyl-3-methylimidazolium chloride withpotassium-1,1,2,3,3,3-hexafluoropropanesulfonate in acetone as describedin Example 10 of U.S. Provisional Patent Application 60/719,370, whichis incorporated in its entirety as a part hereof for all purposes.Similarly, 1-ethyl-3-methylimidazolium1,1,2-trifluoro-2-(pentafluoroethoxy)-ethanesulfonate was synthesized byreacting 1-ethyl-3-methylimidazolium chloride with potassium1,1,2-trifluoro-2-(perfluoroethoxy)ethanesulfonate in acetone accordingto the methods described also in U.S. Provisional Patent Application60/719,370.

The meaning of abbreviations is as follows: “TBAI” meanstetrabutylammonium iodide, “THF” means tetrahydrofuran, “EtOAc” meansethyl acetate, “h” means hour(s), “min” means minute(s), “mL” meansmilliliter(s), “g” means gram(s), “mmol” means millimole(s) and “NMR”means nuclear magnetic resonance spectroscopy. The term “brine” as usedherein denotes a saturated solution of sodium chloride in water.

Example 1

To a solution of potassium cyanide (0.224 g, 3.587 mmol) in water (7.00mL) was added concentrated H₂SO₄ until pH of the solution reached 8. Thesolution was then cooled in an ice bath, and epichlorohydrin was thenadded dropwise (0.22 mL, 0.281 mmol). Five minutes later, the bath wasremoved, and the mixture was allowed to reach room temperature over 12h. 1-butyl-3-methylimidazolium hexafluorophosphate (6.00 ml) was thenadded, followed by tetrabutylammonium iodide (0.097 g, 0.262 mmol). Thebiphasic mixture was heated to 45° C. for one hour. After that time,potassium cyanide was added in eight portions, 0.016 g (0.248 mmol)each, one portion every 30 minutes. After the final cyanide addition,the reaction mixture was heated to 65° C. for two hours. The mixture wasthen cooled to room temperature and the layers were separated. The ionicliquid layer was extracted with brine (3.0 mL) once. Mixed aqueouslayers were extracted with THF (4 portions, 5 mL each). The combinedorganic extracts were dried over Na₂SO₄ and concentrated in vacuo.Purification by column chromatography (hexanes: EtOAc=3:2 to hexanes:EtOAc=1:1 produced pure 3-hydroxyglutaronitrile (0.247 g, 80% isolatedyield).

Example 2

To a cooled (0° C.) solution of KCN (2.04 g, 31.3 mmol) in water wasadded sulfuric acid until the pH of the solution was 8. Epichlorohydrin(2.31 g, 25.0 mmol) was then added and the mixture allowed to reach roomtemperature over 11 h. Tetrabutylammonium iodide (0.920 g, 2.5 mmol) andionic liquid [BMIM]PF₆ (10.0 mL) were then added to the reactionmixture, and the resulting biphasic mixture was heated to 45° C. Afterone hour, KCN was added in 8 portions of 0.130 g (20 mmol) each, oneportion every 30 min. After the final cyanide addition, the mixture wasleft stirring at 45° C. for 45 min. The mixture was then cooled to roomtemperature, and the layers were separated. The water layer wasextracted with ethyl acetate. Organic extracts were concentrated, andthe residue was purified by column chromatography to yield 3-HGN as ayellow oil (80% isolated yield)

Example 3

To a biphasic mixture of water (2.00 mL) and 1-butyl-3-methylimidazoliumhexafluorophosphate (2.00 mL) was added 4-chloro-3-hydroxybutanenitrile(0.079 g, 0.660 mmol), followed by TBAI (0.025 g, 0.067 mmol), andpotassium cyanide (0.007 g, 0.104 mmol). The mixture was heated to 45°C. Every 30 min, potassium cyanide (˜0.004 g, 0.061 mmol) was added,with a total amount of potassium cyanide being 0.046 g (0.706 mmol). Themixture was then heated to 65° C. for two hours. The mixture was thencooled to room temperature and the layers were separated. The waterlayer was diluted with brine (5.0 mL) and was then extracted with THF (3portions, 5 mL each). The organics were then dried over Na₂SO₄ andconcentrated. Purification by column chromatography (hexanes EtOAc=1:1)produced pure 3-HGN (0.060 g, 82% isolated yield).

Example 4

To a biphasic mixture of water (4.00 mL) and 1-butyl-3-methylimidazolium2-H-perfluoropropane sulfonate (4.00 mL) was added4-chloro-3-hydroxy-butanenitrile (0.109 g, 0.912 mmol), followed by TBAI(0.047 g, 0.126 mmol), and potassium cyanide (0.007 g, 0.104 mmol). Themixture was heated to 45° C. Every 30 min, potassium cyanide (˜0.006 g,0.096 mmol) was added, with a total amount of potassium cyanide being0.062 g (0.957 mmol). The mixture was then heated to 65° C. for twohours. The mixture was then cooled to room temperature and the layerswere separated. The water layer was diluted with brine (5.0 mL) and wasthen extracted with THF (3 portions, 5 mL each). The organics were thendried over Na₂SO₄ and concentrated. Purification by columnchromatography (hexanes: EtOAc=1:1) produced pure 3-HGN (0.045 g, 47%isolated yield).

Example 5

To a biphasic mixture of water (3.00 mL) and 1-ethyl-3-methylimidazolium1,1,2-trifluoro-2-(pentafluoroethoxy)-ethanesulfonate (3.00 mL) wasadded 4-chloro-3-hydroxy-butanenitrile (0.299 g, 2.500 mmol), followedby TBAI (0.090 g, 0.250 mmol), and potassium cyanide (0.018 g, 0.275mmol). The mixture was heated to 45° C. Every 30 min, potassium cyanide(˜0.018 g, 0.275 mmol) was added, with a total amount of potassiumcyanide being 0.180 g (2.750 mmol). The mixture was then heated to 65°C. for two hours. The mixture was then cooled to room temperature andthe layers were separated. The water layer was diluted with brine (5.0mL) and was then extracted with THF (3 portions, 5 mL each). Theorganics were then dried over Na₂SO₄ and concentrated. Purification bycolumn chromatography (hexanes: EtOAc=1:1) produced pure 3-HGN (0.220 g,80% isolated yield).

Example 6

To a biphasic mixture of water (3.00 mL) and 1-hexyl-3-methylimidazoliumhexafluorophosphate (3.00 mL) was added 4-chloro-3-hydroxy-butanenitrile(0.299 g, 2.500 mmol), followed by TBAI (0.090 g, 0.250 mmol), andpotassium cyanide (0.018 g, 0.275 mmol). The mixture was heated to 45°C. Every 30 min, potassium cyanide (˜0.018 g, 0.275 mmol) was added,with a total amount of potassium cyanide being 0.180 g (2.750 mmol). Themixture was then heated to 65° C. for two hours. The mixture was thencooled to room temperature and the layers were separated. The waterlayer was diluted with brine (5.0 mL) and was then extracted with THF (3portions, 5 mL each). The organics were then dried over Na₂SO₄ andconcentrated. Purification by column chromatography (hexanes: EtOAc=1:1)produced pure 3-HGN (0.228 g, 81% isolated yield).

Example 7

To a flask containing water (1.50 mL) and 1-methyl-3-butylimidazoliumhexafluorophosphate (1.50 mL) were added 3-hydroxy-4-chlorobutanenitrile(0.359 g, 3.000 mmol) and tetrabutylammonium iodide (0.111 g, 0.300mmol). The biphasic mixture was stirred and triethylamine (0.042 mL,0.300 mmol) and acetone cyanohydrin (0.091 mL, 0.990 mmol) were added.The mixture was warmed to 45° C. Every 30 min, one portion of about0.042 mL (0.300 mmol) triethylamine and about 0.091 mL (0.990 mmol)acetone cyanohydrin was added to the reaction mixture until nine suchportions had been added, so that with the total amount of triethylamineadded was 0.418 mL (3.000 mmol), and the total amount of acetonecyanohydrin added was 0.906 mL (9.900 mmol). The mixture was then heatedto 65° C. for one hour. Thin layer chromatography analysis of thereaction mixture revealed ˜50% of it was the desired product, 3-HGN.

Control A

To a biphasic mixture of water (1.00 mL) and ethyl acetate (1.00 mL) wasadded 4-chloro-3-hydroxy-butanenitrile (0.177 g, 1.481 mmol), TBAI(0.054 g, 0.145 mmol), and potassium cyanide (0.011 g, 0.170 mmol), andthe mixture was heated to 65° C. Every 30 min, potassium cyanide (˜0.011g, 0.170 mmol) was added, with a total amount of potassium cyanide being0.110 g (1.700 mmol). The mixture was cooled after the addition and thelayers were separated. The water layer was extracted with ethyl acetateten times. Combined organic extracts were washed with saturated aqueousNH₄Cl and brine, dried over Na₂SO₄ and dried in vacuo. NMR analysis ofthe residue revealed 0.057 g of 3-hydroxyglutarinitrile (35% isolatedyield).

Where a range of numerical values is recited herein, the range includesthe endpoints thereof and all the individual integers and fractionswithin the range, and also includes each of the narrower ranges thereinformed by all the various possible combinations of those endpoints andinternal integers and fractions to form subgroups of the larger group ofvalues within the stated range to the same extent as if each of thosenarrower ranges was explicitly recited.

Where a range of numerical values is stated herein as being greater thana stated value, the range is nevertheless finite and is bounded on itsupper end by a value that is operable within the context of theinvention as described herein. Where a range of numerical values isstated herein as being less than a stated value, the range isnevertheless bounded on its lower end by a non-zero value.

What is claimed is:
 1. A process for preparing 3-hydroxyglutaronitrilecomprising the steps of: a. providing a biphasic mixture of water and anionic liquid; b. adding to the mixture a compound as described generallyby Formula (II):

wherein X is a leaving group; c. adding a CN— source and, optionally, aphase transfer catalyst to the mixture; and d. adding additional CN—continuously at a rate at which the pH of the solution is maintained atless than about 12, or discontinuously in more than one discreteportion.
 2. The process of claim 1 wherein the CN— source comprises analkali cyanide, trimethylsilyl cyanide or acetone cyanohydrin.
 3. Theprocess of claim 1 wherein X is selected from the group consisting ofCl, Br, I, acetate, tosylate and mesylate.
 4. The process of claim 1wherein the ionic liquid is selected from the group consisting of1-butyl-3-methylimidazolium hexafluorophosphate,1-butyl-3-methylimidazolium 2-H-perfluoropropane sulfonate,1-butyl-3-methylimidazolium tetrafluoroborate,1-ethyl-3-methylimidazolium1,1,2-trifluoro-2-(pentafluoroethoxy)-ethanesulfonate, and1-hexyl-3-methylimidazolium hexafluorophosphate.
 5. The process of claim1 wherein the solution comprises a phase transfer catalyst.
 6. Theprocess of claim 1 wherein, in step (e), the additional CN— is added in8 to 10 portions.
 7. The process of claim 1 wherein one portion of CN—is added every 15 to 30 minutes.
 8. The process of claim 1 wherein3-hydroxyglutaronitrile is subjected, without recovery from the reactionmixture, to conversion to a compound, monomer, oligomer or polymer.
 9. Aprocess according to claim 1 further comprising a step of subjecting the3-hydroxyglutaronitrile to a reaction to prepare therefrom a compound,monomer, oligomer or polymer.
 10. A process according to claim 9 whereina polymer prepared comprises apyridobisimidazole-2,6-diyl(2,5-dihydroxy-p-phenylene)polymer, or apoly[(1,4-dihydrodiimidazo[4,5-b:4′,5′-e]pyridine-2,6-diyl)(2,5-dihydroxy-1,4-phenylene)]polymer.